Functional imaging with Positron Emission Tomography (PET) permits the study of neuroreceptor systems non-invasively in the living human brain, and thus offers a means to evaluate brain-behavior relationships. This application for an Academic Career Development Award (K07) proposes the use of PET to study central serotonin (5HT) markers in normal aging and age-related neuropsychiatric disorders. The candidate is a Neuroradiologist and Nuclear Medicine physician with a foundation in brain imaging techniques including neuroreceptor PET studies, and limited experience in psychiatric and neurological mechanisms of aging. Receptor PET imaging has enormous potential to elucidate the pathogenesis of symptoms of mood dysregulation and cognitive disorders of aging and to guide design of future therapeutic approaches. Interest in the 5HT system is based on evidence of serotonergic dysfunction in several conditions affecting the elderly, including major depression and Alzheimer's disease (AD). Much of the literature describing alterations in the 5HT system in these conditions has been derived from studies of post-mortem tissue, which are complicated by tissue preparation artifacts and a bias toward reflecting end-stage disease. In vivo PET imaging with new selective radioligands for the serotonin type 2 (5HTT2) receptor and 5HT uptake site will be conducted to evaluate 5HT as a marker of neurodegeneration and its relation to clinical psychiatric symptomatology in normal aging, late-life depression, and AD. This imaging has been made more accurate by several techniques developed by the candidate to correct for the confounding effect of neuronal loss on PET measurements. She will examine the mechanism of serotonergic loss in normal aging and possible 5HT2 receptor up-regulation in late-life depression. Investigation of both presynaptic and post-synaptic elements of the 5HT system in vivo will also potentially shed light on a key etiologic debate over the 5HT deficit in AD as a primary degeneration of 5HT neuron vs. the result of cortical degeneration with retrograde loss of ascending 5HT fibers. Characterization of the serotonergic defect in these groups may enhance our understanding of the relationship between AD and depression. Therefore, the goal of this application is to apply PET imaging with newly developed ligands for pre- and post-synaptic 5HT sites to investigate the interplay between behavior in mood and cognitive disorders and alterations in serotonin, and to assess the impact of clinical interventions. This project, combined with laboratory and clinical experience and coursework, will serve as a vehicle for development of the candidate's potential as an investigator of neuropharmacological aspects of aging with a focus on geriatric mood disorders and dementia of the Alzheimer type.